Structure of GTP cyclohydrolase I fromListeria monocytogenes, a potential anti-infective drug target

Abstract

A putative open reading frame encoding GTP cyclohydrolase I fromListeria monocytogeneswas expressed in a recombinantEscherichia colistrain. The recombinant protein was purified and was confirmed to convert GTP to dihydroneopterin triphosphate (Km= 53 µM;vmax= 180 nmol mg−1 min−1). The protein was crystallized from 1.3 Msodium citrate pH 7.3 and the crystal structure was solved at a resolution of 2.4 Å (Rfree= 0.226) by molecular replacement using human GTP cyclohydrolase I as a template. The protein is aD5-symmetric decamer with ten topologically equivalent active sites. Screening a small library of about 9000 compounds afforded several inhibitors with IC50values in the low-micromolar range. Several inhibitors had significant selectivity with regard to human GTP cyclohydrolase I. Hence, GTP cyclohydrolase I may be a potential target for novel drugs directed at microbial infections, including listeriosis, a rare disease with high mortality.